Novel tricycloimidazoline derivatives method for production and use thereof as medicaments

ABSTRACT

The invention relates to compounds of general formula (1) in which R1=H, F or OCH 3  and may occupy the 2, 3, 4 or 5 position on the aromatic carbocycle, R2=H or CH 3 , R3=H, CH 3 , OH or OCH 3 , R4=H and R3 and R4 together can be a carbonyl group (C=0), the addition salts and optionally the hydrates of additional salts with pharmaceutically-acceptable mineral or organic acids and the isomers and tautomers thereof.

The present invention relates to novel tricyclic derivatives substitutedwith a 4,5-dihydro-1H-imidazole group. The compounds of the inventioninteract selectively with presynaptic and/or postsynaptic alpha-2 typeadrenergic receptors (J. Neurochem. 2001, 78, 685-93), on which theybehave like partial agonists, antagonists or inverse agonists. As such,the compounds of the invention are therefore potentially useful in thetreatment of pathologies or conditions sensitive to an adrenergicregulation controlled by the adrenergic alpha-2 receptors. The list ofpathologies considered as being sensitive to such regulation isexcessively long. However, the field of application of the presentinvention is limited to the treatment of neurodegenerative diseases andalso to the treatment of the evolution of said diseases(Psychopharmacology 1996, 123(3), -239-49; Prog. Neuro-Psychopharmacol.Biol. Psychiatry, 1999, 23(7), 1237-46; FR 2 789 681; WO 98/35670;WO-98/06393; WO 95/00145; WO 94/13285), in particular to the treatmentof Alzheimer's disease or to the treatment of the, evolution ofAlzheimer's disease (U.S. Pat. No. 5,281,607; FR 2 795 727; WO 95/01791;WO 94/15603).

Alzheimer's disease is the progressive degenerative disease that is mostwidespread in the elderly population. It is estimated that more than: 15million people are affected (New Engl. J. Med. 1999, 341(22), 1670-79;Drug Benefit Trends 2001, 13/7, 27-40). At the present time,acetylcholinesterase inhibitors (e.g. tacrine, donepezil, rivastigmineand galantamine) constitute the main therapeutic strategy. However, thistherapeutic approach is purely symptomatic and therapeutic benefitsobtained are, to say the most, modest (Drugs 2001, 61/1, 41-52). Sinceeffective therapeutic options against Alzheimer's disease are limited(Curr. Opin. Invest. Drugs 2001, 2(5), 654-56), the discovery of noveltreatments involving molecules endowed with a mechanism of actiondifferent than that of the molecules currently clinically available andcapable of treating or delaying the evolution of the disease is thushighly desirable.

It has been shown, in vitro and in animals, that a substance thatactivates the noradrenergic system can counter the progress of neuronedegeneration (J. Neuro-physiol. 1998, 79(6), 2941-63; Pharmacol.Biochem. Behav. 1997, 56(4), 649-55; J. Cereb. Blood Flow Metabolism1990, 10(6), 885-94) and, furthermore, has the property of stimulatingneuronal growth (J. Comp. Neurol. 1974, 155(1), 15-42; Neuroscience1979, 4(11), 1569-82; Neuroreport 1991, 2, 528-8). It follows thatcompounds with antagonist or inverse agonist properties on theadrenergic alpha-2 receptors, in particular on the presynaptic alpha-2receptors, may be useful in the treatment of neurodegenerative diseases.Given the therapeutic potential of compounds endowed with antagonist orinverse agonist, activity for the adrenergic alpha-2 receptors, thediscovery of novel structures endowed with such properties is highlydesirable. In this respect, the Applicant has discovered that tricyclicderivatives substituted with a 4,5-dihydro-1H-imidazole group interactselectively with the adrenergic receptors of the alpha-2 subtype, onwhich they behave like antagonists or inverse agonists.

Many presynaptic and/or postsynaptic antagonists and/or partialantagonists of the adrenergic alpha-2 receptors are known and describedin the literature. Although the compounds under consideration belong todifferent chemical classes (Idrugs 2001, 4(6), 662-76), some comprise intheir chemical structure a common unit of the 4,5-dihydro-1H-imidazoletype. Among these compounds, examples that may be mentioned includecompounds of the type:

-   dihydroisoindolemethyl- (EP 275 639; EP 313 288; EP 413 433; U.S.    Pat. No. 4,959,374; WO 93/09113 and Eur. J. Pharmacol. 1989, 168(3),    381-6);-   2,3-dihydroindole- (FR 2 577 223; U.S. Pat. No. 4,908,376 and U.S.    Pat. No. 4,912,125);-   5,6-dihydrothieno[3,4-c]pyrrolmethyl- (EP 682 028);-   1,2,4,5-tetrahydro-1H-pyrrolo[3,2,1]indole- (FR 2 583 048; FR 2 611    717; DE 4 325 491 and Life Sci. 1998, 62(9), 839-52);-   1,2,3,4-tetrahydroisoquinolinemethyl- (J. Med. Chem. 1990, 33(2),    596-600);-   1,2,3,4-tetrahydroquinoline- (U.S. Pat. No. 5,017,584; JP 60-058 976    and FR 2 576 308);-   2,3-dihydrobenzochromene- (Heterocycles 2001, 55(2), 387-92);-   1,4-benzodioxane- (EP 33 655; EP 58 006; EP 92 328; Neurochem. Int.    1996, 30(1), 47-53 and Mol. Neuropharmacol. 1992, 1(4), 219-24);-   1,4-benzodioxanemethyl- (EP 74 711);-   4H-1,3-benzodioxine- (J. Pharmacol. Exp. Ther. 1995, 272(2), 681-8);-   2,3-dihydro-1,4-benzoxathiine- (Eur. J. Med. Chem. 1987, 22(4),    273-6);-   2H-1-benzopyrane- and naphthalene- and 3,4-dihydronaphthalene-    (Bioorg. Med. Chem. 1997, 5(5), 843-56);-   dibenzo[1,4]dioxepine- and dibenzopyrane- (Eur. J. Med. Chem. 1991,    26(2) 207-13);-   2,3-dihydro-2-benzofuran- (U.S. Pat. No. 4,411,908 and WO-92/05171);-   furopyridin-efaroxan analogs (Heterocycles 1998, 48(12), 2529-34);-   2-benzofuran- (Eur. J. Pharmacol. 1996, 304(1-3), 221-29 and Eur. J.    Pharmacol. 1998, 353(1), 123-35);-   1-hydroxy-2-phenoxy-2-phenylethyl- (Eur. J. Med. Chem. 1990, 25(9),    757-63;-   phenoxyphenylethyl- (EP 423 802);-   cirazoline analogs (Bioorg. Med. Chem. 2000, 8(5), 883-88);-   phentolamine analogs (Med. Chem. Res. 1997, 7(1), 53-65);-   medetodimine analogs (J. Med. Chem. 1992, 35(4), 750-5);-   2-hydroxyindane- (Bioorg. Med. Chem. 2000, 8(8), 1861-69);-   2,3-dihydro-1H-indene (FR 2 542 738 and J. Med. Chem. 1988, 31(5),    944-48);-   3,4-dihydro-2-naphthalenemethyl- and 2-naphthalenemethyl- and    2H-1-benzopyranemethyl- and benzofuranmethyl- and indenemethyl- and    indanemethyl- (EP 1 010 693);-   quinoxaline- (ES 2 009 246);-   benzospiroalkene- (EP 0 635 497);-   bicyclo[4,2,0]-1,3,5-octatriene- (U.S. Pat. No. 4,567,181).

It is also noteworthy that some of the compounds mentioned above haveonly relatively minor structural differences. Publication J. Med. Chem.2001, 44(5), 787-805 describes compounds whose carbon skeleton is of the1a,2,3,3a,7a,7b-hexahydro-1H-cyclopropa[a]-naphthalene type (figure a):

the carbon-based polycycle is linked to a heterocycle of the4-(4,5-dihydro-1H-imidazole) type via a mono-methylene (CH₂) bridge. Allthe compounds of the invention-have a carbon-based skeleton of the1a,6-dihydro-1H-cyclopropa[a]indene type directly linked to aheterocycle of the 2-(4,5-dihydro-1H-imidazole) type. These structuraldifferences (i.e. size of the carbon-based polycyclic system, number ofcoupling members in the carbocycle-heterocycle junction, isomerism ofthe nitrogen heterocycles) induce significant differences in theirpharmacological profiles. For example, under ordinary temperatureconditions, the conformational mobility inherent to the structure of thecompounds represented by figure a is very much higher than that of thecompounds of the invention. This results in different activity profiles.Thus, for example, the compounds of the invention interact selectivelywith the adrenergic alpha-2 receptors, whereas the compounds describedin J. Med. Chem. 2001, 44(5), 787-805 also interact with the serotoninuptake sites.

The closest state of the art is represented by compounds of thepolycyclic indanylimidazole type (WO 01/85698) corresponding to thefollowing formula (figure b):

in which, inter alia:

-   -   A can form, with the two carbon atoms to which it is attached, a        3-membered carbon-based monocycle;    -   m may be 0 or 1;    -   R2 may be a (C₁₋₆)alkyl group;    -   t may be 0 or 1;    -   t is 1 and R1 may be a halogen or a (C₁₋₆) alkyloxy group;    -   R3 may be a hydrogen, OH, ═O, (C₁₋₆)alkyl or (C₁₋₆)alkyloxy;        the compounds represented above and the compounds of the present        invention thus differing in, the nature of their nitrogen        heterocycle. In this respect, it is known to a person skilled in        the art familiar with the field that the nature of the nitrogen        heterocycle constitutes one of the major determining factors of        the pharmacological activity profile of the ligand. Given the        large number of structures involving a 4,5-dihydro-1H-imidazole        unit, which are already known for their adrenergic alpha-2        properties, it is surprising that the        2-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole        unit gives the compounds of the invention a quite unique        pharmacological profile. Specifically, in vitro, the following        is shown:    -   selectivity of the compounds of the invention for the human        alpha-2A versus human alpha-2B subtype. This characteristic is        important since the intended indication involves a central        action of the product in cerebral structures in which the        alpha-2B sites do not appear to be preferentially distributed        (Eur. J. Pharmacol. 1999, 366(1), 35-0.39; Nature 1999, 402,        181-83). An interaction with the alpha-2B subtypes thus tends to        increase above all the probability of appearance of adverse        effects;    -   intrinsic activity of the inverse agonist type of the compounds        of the invention on the alpha-2A receptors, which is thus        different than that of the compounds claimed in WO 01/85698.

Furthermore, it is shown, in vivo, that the products of the inventionare capable of countering the effect of scopolamine in a test of memorydeficit considered as a representative animal model of the memorydisorders that are manifested during Alzheimer's disease(Psychopharmacology 1992, 106, 26-30; Exp. Neurol. 2000, 163, 495-529).The compounds of the invention, endowed with such an activity profile,are therefore potentially useful for treating diseases or disorders thatare sensitive to the action of partial: agonists, antagonists or inverseagonists of the adrenergic alpha-2 receptors, for instanceneurodegenerative diseases for which there is a strong therapeutic need.

Finally, the process for preparing the compounds of the invention isdifferent than that for the compounds claimed in WO 01/85698 andinvolves novel reaction intermediates.

More specifically, a subject of the present invention is novel2-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazolederivatives, which, in base form, correspond to the general formula (1):

in which:

-   -   R1 represents a hydrogen atom, a fluorine atom or a methoxyl        (OCH₃) group. The substituent R1 on the aromatic carbocycle may        be in position 2, 3, 4 or 5;    -   R2 represents a hydrogen atom or a methyl group;    -   R3 represents a hydrogen atom, a methyl group, a hydroxyl group.        (OH) or a methoxyl group (OCH₃);    -   R4 is a hydrogen atom;    -   R3 and R4 together represent a carbonyl group (C═O); the        addition salts thereof and optionally the hydrates of the        addition salts with pharmaceutically acceptable mineral acids or        organic acids, and also the tautomeric forms, thereof, the        enantiomers- and mixtures of enantiomers and the stereoisomers        in pure form or in the form of a racemic or non-racemic mixture.

In one particular embodiment of the invention, the compounds of formula(1) in which:

-   -   R1 and R2 have the same meaning as above;    -   R3 represents a methyl group, a hydroxyl group (OH) or a        methoxyl group (OCH₃);    -   R4 is a hydrogen atom;    -   the substituents R3 and 4,5-dihydro-1H-imidazole are in        anti-periplanar positions relative to the plane defined by the        indane ring system;        are in all cases the preferred stereoisomers of the products of        the invention.

In another particular embodiment of the invention, the compounds offormula (1) in which:

-   -   R1 has the same meaning as above;    -   R2 represents a methyl group;    -   R3 represents a hydrogen atom, a methyl group, a hydroxyl group        (OH) or a methoxyl group (OCH₃);    -   R4 is a hydrogen atom;    -   R3 and R4 together represent a carbonyl group (C═O);    -   the substituents R2 and 4,5-dihydro-1H-imidazole are in        syn-periplanar positions relative to the plane defined by the        cyclopropane ring;        are in all cases the preferred stereoisomers of the products of        the invention.

By the term “anti-periplanar” the inventors mean the relativeconfigurations of the molecules (1) for which the substituents R3 and4,5-dihydroimidazole are on either side of the plane defined by theindane ring system. By the term “syn-periplanar”, the inventors mean therelative, configurations of the molecules (1) for which the substituentsR2 and 4,5-dihydroimidazole are on the same side of the plane defined bythe cyclopropane ring.

The compounds of general formula. (1) may exist in several tautomericforms. Although not explicitly reported in the present patentapplication, to simplify the graphic representation of the structuralformulae, such tautomeric forms are nevertheless included in the fieldof application of the invention. The compounds of the invention compriseseveral asymmetric carbon atoms in their structure.

As a result, they exist in the form of enantiomers and diastereoisomers.The invention relates not only to each pure stereoisomer, i.e. combinedwith less than 5% of another stereoisomer or of a mixture of otherstereoisomers, but also to the mixture of one or more stereoisomers inall proportions. The compounds of the invention may thus intervene aspure stereoisomers or racemic or non-racemic mixtures of stereoisomers.

Finally, the invention covers the process for preparing the derivativesof general formula (1).

The derivatives of general formula (1) may be obtained by the processdescribed in the scheme illustrated in appendix 1. The preparation ofthe compounds of the invention uses as starting material suitable2-bromo-benzaldehydes, of formula (1), which are commercially availableor known in the literature (i.e. RN 6630-33-7; RN 10401-18-0; RN43192-31-0; RN 7507-80-0; RN 126712-07-0; RN 59142-68-6; RN 94569-84-3;RN 360575-28-6 or prepared by reduction of the corresponding acid RN132715-69′-6). The derivatives of the 2-ethenyl type of formula (II-1)are obtained via a Wittig reaction performed usingmethyltriphenylphosphonium bromide in basic medium. The derivatives ofthe 2-(1-propenyl)-type of formula (II-2) and of (E) stereochemistry areprepared selectively in 2 steps according to the method described inTetrahedron 1995, 51(37), 10115-24: addition of ethylmagnesium bromideto the aldehyde function followed by a dehydration reaction of thesecondary alcohol obtained in acidic medium. The introduction of thecarboxylic acid function onto the derivatives of formula (II) isperformed by means of a bromine-lithium exchange reaction followed bytrapping the organolithium reagent formed using CO₂. The2-ethenylbenzoic acids (III-1) and (E)-2-(1-propenyl)benzoic acid(III-2) are compounds that are known in the literature (RN 27326-43-8and RN 68692-67-1, respectively). The derivatives of formula (III),activated either in acyl chloride form or in amide form (IV), Synlett1994, 2, 105-6, are converted into β-keto esters (V) by applying amethod similar to that described in Synthesis 1993, 3, 290-92. The keyintermediate in the preparation of the compounds of the invention is the6-oxo-1a,6-dihydro-1H-cyclopropa[a]indene-6a-carboxylic acid ester offormula (VII). This ester is obtained by intramolecular addition of acarbenoid onto the double bond according to Doyle, M. P.; McKervey, M.A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with DiazoCompounds, John Wiley & Sons, Inc. 1998, chapter 5, pages 238-288. Thecarbenoid is obtained by decomposition of a precursor of the diazo type(VI), which is itself prepared from the 3-oxo-3-(2-enyl-aryl)propionicacid esters of formula (V) according to the method described in Synth.Commun. 1987, 17(4), 1709-16.

Starting with the compound of formula (VII), all the compounds of theinvention are prepared. Thus, the compounds (X) in which: R1 is H, F orOCH₃; R2 is H or CH₃; R3 is CH₃ and R₄ is H are obtained by:methylenation of (VII) using methyltriphenylphosphonium bromide in thepresence of a base according to a standard Wittig reaction; reduction ofthe exocyclic double bond formed using the diimide according to aprocedure similar to that described in Tetrahedron 1976, 32, 2157-62 andcondensation of ethylenediamine in the presence of trimethylaluminumonto the esters (IX) according to a technique described in J. Org. Chem.1987, 46, 2824-26.

The compounds of formulae (XII, XIII and XV) in which: R1 is H, F orOCH₃; R2 is H or CH₃; R3 is OH, OCH₃; R4 is H or R3 and R4 together forma carbonyl group (═O) are, or their part, prepared from the intermediate(VII). Thus, the 6-oxo function of (VII) may be reduced to the alcohol(XI) by means, for example, of a hydride donor. The reduction withsodium borohydride in cold ethanol is diastereoselective; the isomer inwhich the hydroxyl (OH) and cyclopropane groups are in syn-periplanarpositions relative to the plane defined by the indane ring system is theonly one observed in the reaction under consideration. The secondaryalcohol (XI) may, then be either directly converted into the expectedheterocycle (XII), route a, appendix 1; or methylated to the ether (XIV)and then converted into the expected heterocycle (XV), route b, appendix0.1. Oxidation of the alcohols of formula (XII) gives the compounds offormula (XIII).

The compounds of formula (XVI) in which: R1 is H, F or OCH₃; R2 is H orCH₃; R3 and R4 are H, are derived from the total reduction of the 6-oxofunction of the compound of formula (VII) according to a method similarto that described in J. Org. Chem. 1973, 38(15), 2675-81. The nitrogenheterocycle contained in (XVII) is then formed as described previously.

The compounds of formulae (X), (XII), (XIII), (XV) and (XVII) constituteall the compounds of the invention.

A subject of the invention is also pharmaceutical compositionscontaining, as active principle, at least one of the derivatives ofgeneral formula (1) or a salt thereof or hydrates of salts thereof incombination with one or more inert supports or other pharmaceuticallyacceptable vehicles.

The pharmaceutical compositions according to the invention may be, forexample, compositions for oral, nasal, sublingual, rectal or parenteraladministration. As examples of compositions for oral administration,mention may be made of tablets, gel capsules, granules, powders and oralsolutions or suspensions.

The formulations that are suitable for the chosen administration formare known and described, for example, in: Remington, The Science andPractice of Pharmacy, 19th edition, 1995, Mack Publishing Company.

The effective dose of a compound of the invention varies as a functionof numerous parameters, for instance the chosen route of administration,the weight, age, sex, degree of advancement of the pathology to betreated and sensitivity of the individual to be treated. Consequently,the optimum dosage will have to be determined, as a function of theparameters considered pertinent, by the specialist in the art. Althoughthe effective doses of a compound of the invention can vary within largeproportions, the daily doses may range between 0.01 mg and 100 mg per kgof body weight of the individual to be treated. A daily dose of acompound of the invention of between 0.10 mg and 50 mg per kg of bodyweight of the individual to be treated is, however, preferred.

The pharmaceutical compositions according to the invention, are usefulin the treatment of neurodegenerative diseases.

EXAMPLES

The examples that follow illustrate the invention but do not limit it inany way.

In the examples and the reference examples below:

-   (i) the reaction progress is monitored by thin layer chromatography    (TLC) and consequently the reaction times are mentioned only as a    guide;-   (ii) different crystalline forms may give different melting points;    the melting points reported in the present patent application are    those of the products prepared according to the method described and    are uncorrected;-   (iii) the structure of the products obtained according to the    invention is confirmed by the nuclear magnetic resonance (NMR) and    infrared (IR) spectra and the elemental analysis, the purity of the    final products is checked by TLC, and the enantiomeric purity of the    reaction intermediates and final products is determined by    chiral-phase HPLC;-   (iv) the NMR spectra are recorded in the solvent indicated. The    chemical shifts (δ) are expressed in parts per million (ppm)    relative to tetra-methylsilane. The multiplicity of the signals is    indicated by: s, singlet; d, doublet; t, triplet; q, quartet; m,    multiplet; b, broad;-   (v) the various symbols of the units have their usual meaning: μg    (microgram); mg (milligram); g (gram); ml (milliliter); mV    (millivolt); ° C. (degrees Celsius); mmol (millimole); nmol    (nanomole); cm (centimeter); nm (nanometer); min (minute); ms    (millisecond), Hz (hertz); [α] (specific optical rotation measured    at 5.89 nm, 25° C. and at a concentration c, in the present    invention the dimension deg cm² g⁻¹ is always implied); the    pressures are given in millibar (mb);-   (vi) the abbreviations have the following meanings: mp (melting    point); bp (boiling point); AUC (area under the curve);-   (vii) the term “room temperature” means a temperature of between    20° C. and 25° C.

Example 1 Ethyl6-oxo-1a,6-dihydro-1H-cyclopropa[a]-—indene-6a-carboxylate (VII-1)

A solution of 23.06 ml (0.153 mol) of DBU in 35 ml of anhydrous THF isadded dropwise to a solution of 33.42 g (0.153 mol) of ethylortho-vinylbenzoylacetate (V-1), 36.76 g (0.153 mol) ofpara-acetamidobenzenesulfonyl azide and 300 ml of anhydrous THF, whilestirring on an ice bath and under nitrogen. After stirring for 16 hoursat room temperature, the garnet-red solution is poured into a mixture ofsaturated aqueous NH₄Cl solution and ice. The mixture is extracted twicewith ethyl acetate. The organic phases are separated out by settling andwashed with water and then with brine. After drying over MgSO₄ andfiltration, the solvent is evaporated off under vacuum (temperaturebelow 40° C.). The crystalline mass obtained is taken up in a 50/50cyclohexane/ethyl acetate mixture and thepara-acetamidobenzenesulfonylamide is filtered off. The mother liquorsare evaporated to dryness under vacuum (T°<40° C.). The brown oilobtained is purified by rapid filtration on 200 g of silica using CH₂Cl₂as solvent. After removal of the solvent (T°<40° C.), 35.81 g (95.8%) ofan orange-colored oil are obtained, and are used directly in thecycloaddition reaction.

The solution of the diazoacetate (VI-1) obtained previously in 50 ml ofanhydrous CH₂Cl₂ is introduced dropwise to a suspension of 1.18 g ofrhodium acetate and 250 ml of anhydrous CH₂Cl₂, with stirring at roomtemperature. After stirring overnight at room temperature, the catalystis filtered off and the solvent is removed under vacuum. The crudeproduct is purified by chromatography on 320 g of silica, usingcyclohexane containing 10% ethyl acetate as solvent.

The title product is obtained (23.9 g);

Yield: 75.7%

C₁₃H₁₂O₃: 216.24

IR (film) ν: 1720 and 1746 cm¹ (C═O)

¹H NMR (CDCl₃): 1.33 (t, 3H) 1.744 (t, 1H); 2.39 (dd, 1H); 3.37 (dd,1H); 4.29 (q, 2H); 7.35 (t, 1H); 7.45 (d, 1H); 7.51 (t, 1H); 7.70 (d,1H)

¹³C NMR (CDCl₃): 14.13; 32.04; 38.61; 39.77; 61.56; 124.43; 125.31;127.63; 134.11; 134.13; 151.46; 168.50; 195.44.

Example 2 Ethyl 1a,6-dihydro-1H-cyclopropa[a]indene-6a-carboxylate(XVI-1)

1.7 ml (10.64 mmol) of triethylsilane are added dropwise to a solutionof 0.92 g (4.25 mmol) of (VII-1) in 4 ml of trifluoroacetic acid, withstirring, under nitrogen and on an ice bath. After stirring for 4 hoursat room temperature, the solution is poured into an ice/water mixture.After addition of ethyl acetate, the mixture is basified by addition ofsodium bicarbonate with vigorous stirring. The organic phase isseparated out by settling and then washed with water and then withbrine. After drying over MgSO₄ and filtration, the brown oil obtained ispurified by chromatography on silica, using cyclohexane containing 2%ethyl acetate as eluent. The title product is obtained (0.47 g);

Yield: 54.6%

C₁₃H₁₄O₂: 202.24

IR (film) ν: 1721 cm¹ (C═O)

¹H NMR (CDCl₃): 0.68 (t, 1H); 1.27 (t, 3H); 1.98 (dd, 1H); 2.95 (ddd,1H); 3.06 (d, 1H); 3.72 (d, 1H); 4.18 (q, 2H); 7.13 (m, 2H); 7.18 (m,1H); 7.27 (m, 1H).

Example 3 Ethyl1-exo-methyl-1a,6-dihydro-1H-cyclopropa[a]indene-6a-carboxylate (XVI-2)

C₁₄H₁₆O₂: 216.28

IR (film) ν: 1717 cm⁻¹ (C═O)

¹H NMR (CDCl₃): 1.04 (m, 1H); 1.29 (t, 3H); 1.35 (d, 3H); 2.77 (d, 1H,J=4.4 Hz); 3.14 (d, 1H); 3.58 (d, 1H); 4.21 (m, 2H); 7.11 (m, 3H); 7.24(m, 1H).

Example 4 Ethyl6-methylene-1a,6-dihydro-1H-cyclopropa[a]indene-6a-carboxylate (VIII)

2.56 g (21 mmol) of KOtBu are added portionwise to a suspension of 7.5 g(21 mmol) of methyltriphenylphosphonium bromide and 45 ml of anhydrousTHF with stirring at room temperature. The suspension is stirred for 1hour 30 minutes, and a solution of 3.02 g (14 mmol) of (VII-1) in 5 mlof anhydrous THF is then introduced dropwise, with cooling over an icebath. After stirring overnight at room temperature, the suspension ispoured into saturated aqueous NH₄Cl solution and extracted twice withethyl acetate. The organic phases are washed with water and then withbrine. After drying over MgSO₄ and filtration, the solvent is removedunder vacuum. The triphenylphosphine oxide is crystallized fromisopropyl ether and the mother liquors are evaporated to dryness undervacuum. The residual oil is purified by chromatography on silica, usingcyclohexane containing 3% ethyl acetate as eluent. The title product isobtained (1.8 g);

Yield: 59%

C₁₄H₁₄O₂: 214.25

¹H NMR (CDCl₃): 1.04 (t, 1H); 1.30 (t, 3H); 2.16 (dd, 1H); 3.16 (dd,1H); 4.21 (m, 2H); 5.7.3 (s, 1H); 5.84 (s, 1H); 7.19 (m, 2H); 7.30 (m,1H); 7.47 (m, 1H).

Example 5 Ethyl6-methyl-1a,6-dihydro-1H-cyclopropa-[a]indene-6a-carboxylate (IX)

3.65 ml (26 mmol) of triethylamine are added dropwise to a suspension of2.8 g (13 mmol) of (VIII), 5.6 g (26 mmol) of2,4,6-trimethylbenzenesulfonyl hydrazide and 20 ml of anhydrousmethanol, with stirring at room temperature, and the mixture is thenrefluxed for 5 hours. The methanol is removed under vacuum; saturatedaqueous 10% NaHCO₃ solution is added and the mixture is extracted twicewith ether. The organic phases are washed with brine, dried over MgSO₄,filtered and evaporated to dryness under vacuum. The residual oil ispurified by chromatography on silica, using cyclohexane containing 50%dichloromethane as eluent. The title product is obtained (2.19 g);

Yield: 78%

C₁₄H₁₆O₂: 216.27

¹H NMR (CDCl₃): 0.64 (t, 1H); 1.27 (t, 3H); 1.36 (d, 3H); 1.77 (dd, 1H);2.93 (dd, 1H); 4.04 (q, 1H); 4.19 (q, 2H); 7.14 (m, 3H); 7.25 (d, 1H).

Example 6 Ethyl6-hydroxy-1a,6-dihydro-1H-cyclopropa-[a]indene-6a-carboxylate (XI-1)

1.97 g (36.4 mmol) of KBH₄ are added portionwise to a solution of 5.25 g(24.3 mmol) of (VII-1) in 50 ml of absolute ethanol, with stirring on anice bath, the mixture is then stirred overnight while allowing the bathto return to room temperature. The ethanol is removed under vacuum andthe residue is taken up in an ice/water mixture and extracted twice withethyl acetate. The organic phases are washed with brine, dried overMgSO₄, filtered and evaporated to dryness under vacuum. The residue ispurified by chromatography on silica, using cyclohexane containing 20%ethyl acetate as eluent. The title compound is obtained (4.98 g);

Yield: 95%

C₁₃H₁₄O₃: 218.24

IR (film) ν: 3440 cm⁻¹ (OH); 1720 cm⁻¹ (C═O)

¹H NMR (CDCl₃): 1.67 (t, 1H); 1.29 (t, 3H); 1.83 (dd, 1H); 2.34 (d, 1H);3.01 (dd, 1H); 4.22 (m, 2H); 6.03 (d, 1H); 7.22 (m, 3H); 7.31 (m, 1H).

Example 7 Ethyl6-methoxy-1a,6-dihydro-1H-cyclopropa-[a]indene-6a-carboxylate (XIV-1)26.53 g (114.5 mmol) of Ag₂O are added to a solution of

5 g (22.9 mmol) of (XI-1) and 80 ml of anhydrous acetonitrile, withstirring at room-temperature, followed by rapid dropwise addition of7.13 ml (114.5 mmol) of methyl iodide. The suspension is stirred at roomtemperature, in the absence of light, for 48 hours. The suspension isfiltered and the solvent is removed under vacuum. The residual oil ispurified by chromatography on silica, using cyclohexane containing 5%ethyl acetate as eluent. The title compound is obtained (4.3 g);

Yield: 81%

C₁₄H₁₆O₃: 232.27

¹H NMR (CDCl₃): 1.29 (m, 4H); 1.92 (dd, 1H); 2.79 (dd, 1H); 3.57 (s,3H); 4.21 (m, 2H); 5.73 (s, 1H); 7.20 (m, 3H); 7.28 (m, 1H).

Example 8 2-(1a,6-Dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; (XVII-1)

0.23 ml (3.45 mmol) of ethylenediamine is introduced dropwise into asolution of 1.5 ml (3 mmol) of a 2M solution of trimethylaluminum intoluene and 10 ml of anhydrous toluene, with vigorous stirring at −10°C. Stirring is continued at room temperature for 30 minutes, followed bydropwise addition of a solution of 0.47 g (2.3 mmol) of (XVI-1) in 2 mlof anhydrous toluene. The mixture is refluxed for 2 hours. 1.3 ml ofwater are added slowly over an ice bath with vigorous stirring, and themixture is kept at room temperature for 30 minutes. The organic phase isseparated out by settling, diluted with ethyl acetate, washed withbrine, dried (Na₂SO₄) and evaporated to dryness under vacuum. The crudeproduct is purified by chromatography on alumina, using dichloromethanecontaining 2% of methanol. The title product is obtained (0.31 g);

Yield: 67%

C₁₃H₁₄N₂: 198.26

¹H NMR (CDCl₃): 0.70 (t, 1H); 1.51 (dd, 1H); 2.89 (dd, 1H); 3.20 (d,1H); 3.62 (d, 1H); 3.66 (s, 4H); 7.12 (m, 0.2H); 7.17 (m, 114); 7.25 (m,1H).

Oxalate of the title compound:

mp: 1.64-7166° C.

C₁₅H₁₆N₂O₄: 288.29

Calculated %: C, 62.49; H, 5.59; N, 9.72. Found %: C, 62.46; H, 5.72; N,9.66.

¹H NMR (DMSOd₆): 0.93 (t, 1H); 2.03 (dd, 1H); 3.24 (d, 1H); 3.29 (dd,1H); 3.54 (d, 1H); 3.83 (s, 4H); 7.18 (m, 2H); 7.25 (m, 1H); 7.36 (m,1H).

The compounds of formula (XVII-1) are resolved by chromatographicseparation of the diastereoisomeric keto esters (VII-3) of(R)-(−)-pantolactone (RN 599-04-2):

Example 9(+)-2-(1a,6-Dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(+)-(XVII-1)

Hydrochloride of the title compound:

mp: 245-247° C.

C₁₃H₁₅CIN₂: 234.73

Calculated %: C, 66.52; H, 6.44; N, 11.93. Found %: C, 66.34; H, 6.65;N, 11.71

¹H NMR (D₂O): 1.01 (t, 1H); 1.92 (dd, 1H); 3.26 (m, 1H); 3.34 (d, 1H);3.47 (d, 1H); 3.93 (s, 4H); 7.28 (m, 2H); 7.32 (m, 1H); 7.42 (m, 1H).

[α]²⁵ _(D): +218.2° C. (c=0.369, methanol).

Example 10(−)-2-(1a,6-Dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(−)-XVII-1)

Hydrochloride of the title compound:

mp: 245-247° C.

C₁₃H₁₅CIN₂: 234.73

Calculated %: C, 66.52; H, 6.44; N, 11.93. Found %: C, 65.85; H, 6.45;N, 11.69.

¹H NMR (D₂O): 1.01 (t, 1H); 1.92 (dd, 1H); 3.26 (m, 1H); 3.34 (d, 1H);3.47 (d, 1H); 3.93 (s, 0.4H); 7.28 (m, 2H); 7.32 (m, 1H); 7.42 (m, 1H).

[α]²⁵ _(D): −219.90 (c=0.467, methanol).

Example 112-(1-exo-Methyl-1a,6-dihydro-1H-cyclopropa-[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(XVII-2)

Working as in example 8, but using compound (XVI-2) instead of thecompound of formula (XVI-1), the title compound is obtained.

Yield: 30%

C₁₄H₁₆N₂: 212.28

¹H NMR (CDCl₃): 0.88 (m, 1H); 1.22 (d, 3H); 2.57 (d, 1H); 3.19 (d, 1H);3.35 (d, 1H); 3.63 (s, 4H); 7.10 (m, 3H); 7.25. (d, 1H).

Fumarate of the title compound:

mp: 133-135° C.

C₁₈H₂₀N₂O₄: 328.37

Calculated %: C, 65.84; H, 6.14; N, 8.53. Found %: C, 65.51; H, 6.35; N,8.65

¹H NMR (DMSOd₆): 1.08 (m, 1H); 1.17 (d, 3H); 3.15 (d, 1H); 3.29 (d, 1H);3.35 (d, 1H); 3.82 (s, 4H); 6.43. (s, 2H); 7.13 (m, 2H); 7.19 (m, 1H);7.32 (m, 1H).

Example 122-(6-Methyl-1a,6-dihydro-1H-cyclopropa[a]-inden-6a-yl)-4,5-dihydro-1H-imidazole(X)

Working as in example 8, but using compound (IX) instead of the compoundof formula (XVI-1), the title compound is obtained.

Yield: 68%

C₁₄H₁₆N₂: 212.28

¹H NMR (CDCl₃): 0.65 (t, 1H); 1.40 (d, 3H); 1.63 (dd, 1H); 2.81 (dd,1H); 3.65 (s, 4H); 3.97 (q, 1H); 7.16 (m, 3H); 7.23 (m, 1H).

Hydrochloride of the title compound:

Sublimation: 250° C.

C₁₄H₁₇CIN₂: 248.76

Calculated %: C, 67.60; H, 6.89; N, 11.26. Found %: C, 67.18; H, 6.96;N, 11.04.

¹H NMR (D₂O): 0.97 (t, 1H); 1.38 (d, 3H); 1.75 (dd, 1H); 3.15 (dd, 1H);3.82 (q, 1H); 3.92 (s, 4H); 7.27 (m, 3H); 7.31 (m, 1H).

Example 136a-(4,5-Dihydro-1H-imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-6-β-ol(XII-1)

Working as in example 8, but using compound (XI-1) instead of thecompound of formula (XVI-1), the title compound is obtained.

Yield: 27%

C₁₃H₁₄N₂O: 214.26

¹H NMR (DMSOd₆): 1.29 (t, 1H); 1.85 (dd, 1H); 3.19 (dd, 1H); 3.81 (s,4H); 5.76 (s, 1H); 7.22 (m, 2H); 7.28 (m⁻²H).

Hydrochloride of the title compound:

mp: 229-231° C.

C₁₃H₁₅CIN₂O: 250.73

Calculated %: C, 62.28; H, 6.03; N, 11.17. Found %: C, 62.36; H, 6.05;N, 11.29.

¹H NMR (D₂O): 1.41 (t, 1H); 1.84 (dd, 1H); 3.30 (dd, 1H); 3.97 (s, 4H);5.85 (s, 1H); 7.36 (m, 4H).

Example 142-(6-Methoxy-1a,6-dihydro-1H-cyclopropa[a]-inden-6a-yl)-4,5-dihydro-1H-imidazole(XV-1)

Working as in example 8, but using compound (XIV-1) instead of thecompound of formula (XVI-1), the title compound is obtained.

Yield: 51%

C₄H₁₆N₂O: 228.28

¹H NMR (CDCl₃): 1.25 (t, 1H); 1.66 (dd, 1H); 2.75 (dd, 1H); 3.59 (s,3H); 3.64 (s, 4H); 5.61 (s, 1H); 7.18 (m, 3H); 7.27 (m, 1H).

Fumarate of the title compound:

mp: 173-175° C.

C₁₈H₂₀N₂O₅: 344.37

Calculated %: C, 62.78; H, 5.85; N, 8.13. Found %: C, 62.64; H, 5.94; N,8.15.

¹H NMR (DMSOd₆): 1.18 (t, 1H); 2.09 (dd, 1H); 3.08 (dd, 1H); 3.44 (s,3H); 3.75 (s, 4H); 5.68 (s, 1H); 6.44 (s, 2H); 7.17-7.31 (m, 4H).

The resolution is performed by chromatographic separation on a chiralsupport (Chiralpack AD, eluent: hexane containing 5% methanol).

Example 15(+)-2-(6-Methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(+)-(XV-1)

Fumarate of the title compound:

mp: 170-172° C.

C₁₈H₂₀N₂O₅: 344.37

Calculated %: C, 62.78; H, 5.85; N, 8.13. Found %: C, 62.55; H, 5.89; N,8.05.

¹H NMR (DMSOd₆): 1.19 (t, 1H); 2.09 (dd, 1H); 3.09 (dd, 1H); 3.44 (s,3H); 3.75 (s, 4H); 5.67 (s, 1H); 6.44 (s, 2H); 7.19-7.31 (m, 0.4H)

[α]²⁵ _(D): +174.150 (c 0.16, methanol).

Example 16(−)-2-(6-Methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(−)—(XV-1)

Fumarate of the title compound:

mp: 170-172° C.

C₁₈H₂₀N₂O₅: 344.37

Calculated %: C, 62.78; H, 5.85; N, 8.13. Found %: C, 62.45; H, 5.92; N,8.05.

¹H-NMR (DMSOd₆): 1.19 (t, 1H); 2.09 (dd, 1H); 3.09 (dd, 1H); 3.44 (s,3H); 3.75 (s, 4H); 5.67 (s, 1H); 6.44 (s, 2H); 7.19-7.31 (m, 4H)

[α]²⁵ _(D): −164.16°. (c=0.14, methanol).

Example 172-(2,6-Dimethoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(XV-1a)

Working as in example 8, but using compound (XIV-1a) instead of thecompound of formula (XVI-1), the title compound is obtained.

Yield: 55%

C₁₅H₁₈N₂O₂: 258.31

¹H NMR (CDCl₃): 1.31 (t, 1H); 1.68 (dd, 1H); 2.84 (dd, 1H); 3.58 (s,3H); 3.63 (s, broad, 4H); 3.83 (s, 3H); 5.68 (s, 1H); 6.73 (d, 1H); 6.90(d, 1H); 7.14 (t, 1H).

Fumarate of the title compound:

mp: 177-179° C.

C₁₉H₂₂N₂O₆: 374.39

Calculated %: C, 60.95; H, 5.92; N, 7.48. Found %: C, 60.24; H, 6.39; N,7.08.

¹H NMR (DMSOd₆): 1.19 (t, 1H); 2.03 (dd, 1H); 3.05 (dd, 1H); 3.43 (s,3H); 3.74 (s, 4H); 3.80 (s, 3H); 5.64 (s, 1H); 6.45 (s, 2H); 6.86 (m,2H); 7.19 (t, 1H).

Example 182-(3-Fluoro-6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(XV-1b)

Working as in example 8, but using compound (XIV-1b) instead of thecompound of formula (XVI-1), the title compound is obtained.

Example 192-(3-Fluoro-1-exo-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole(XVII-2b)

Working as in example 8, but using compound (XIV-2) instead of thecompound of formula (XVI-1), the title compound is obtained.

The compounds of formula (1) and the therapeutically acceptable saltsthereof have advantageous pharmacological properties.

The results of the tests are collated in the following table:Scopolamine- induced memory Intrinsic deficiency activity amplitude ofAffinity (pKi) % the effect % Compound Alpha-2A Alpha-2B stimulated(dose, mg/kg i.p.) XV-1 7.9 6.5 −2 +168 (2.5)  (+) -XV-1 8.4 <5 −63 —XVII-2 8.5 7.7 −64 +181 (0.63) (−) — — — +100 — adrenalin donepezil — ——  +67 (0.16)Scopolamine- Intrinsic induced Compound Affinity (pKi)-activity memorydeficiency amplitude of % the effect % Alpha-2A Alpha-2B stimulated(dose, mg/kg . . . _(—)_i.p.)—-XV-.l 7.9 6.5- -2+168 (2.5) (+)—XV-18.4<5-63 _XVII-2 8.5 7.7-64+181 (0.63) * (−)- - -: . _‘+’, 100 adrenalindonepezil _+67 (0.16)Binding to the Adrenergic Alpha-2 Receptors:

Membranes of C6 cells permanently expressing either the human alpha-2Aor alpha-2B receptor are prepared in Tris-HCl (pH=7.6). The bindingtests are performed with 2 nM [³H]RX 821002. The incubation medium iscomposed of 0.4 ml of cell membranes (10 μg of proteins), 0.05 ml ofradioligand and 0.05 ml of test product or of phentolamine (10 μM) todetermine the nonspecific binding. The reaction is quenched afterincubation for 30 minutes at 25° C. by adding 3 ml of cold 50 mMTris-HCl (pH=7.6), followed by filtration through Whatman GF/B filtersusing a Brandel. The Ki values are calculated according to the equationKi=IC₅₀/(1+C/Kd) in which C is the concentration and Kd the dissociationconstant, pKi=−logKi. Under these conditions, it is seen that thecompounds of the invention have high affinity for the receptors of thehuman adrenergic alpha-2A subtype, whereas they have little or noaffinity for the receptors of the human adrenergic alpha-2B subtype (cf.above table). This unexpected receptor selectivity of the compounds ofthe invention, compared with the compounds of the prior art, may have afavorable impact on their tolerance.

Measurement of the Activation of the Adrenergic Alpha-2 Receptors:

The responses as GTPγS are performed on membrane preparations in 20 mMHEPES (pH=7.4) with 30 μM of GDP, 100 mM of NaCl, 3 mM of MgCl₂ and 0.2mM of ascorbic acid. The maximum stimulation of the GTPγS is determinedin the presence of 10 mM of (−)-adrenalin and calculated versus thebasal GTPγS response. The results are expressed versus either adrenalinor RX 81105-9. Under these conditions, the compounds of the inventionare distinguished from most of the compounds of the prior art of the4,5-dihydro-1H-imidazole and/or 1H-imidazole type in that they behaverather as inverse agonists on human alpha-2A adrenergic receptors (cf.above table).

Test of Scopolamine-Induced Memory Deficiency:

Scopolamine has amnesiant properties in man and animals. Thus, itsadministration to a healthy person causes certain symptoms similar towhat is observed in Alzheimer's disease. Scopolamine-induced memorydeficiency is thus used as an experimental pharmacological model of thispathology. Scopolamine reduces the capacity for acquisition,memorization and recall in a test of passive avoidance in rats. Thisinvolves measuring the reticence, after learning, that an animal showswith regard to entering a dark compartment where it receives a mildelectric shock. The administration of scopolamine suppresses thisreticence, and the test compounds counter the effect of scopolamine. Theexperimental protocol used is described in Psychopharmacol. 1992, 106,26-30.

The compounds of the invention show considerable activity in this test(cf. above table). The amplitude of the effect obtained with thecompounds of the invention is higher than that, for example, ofdonezepil, an acetylcholinesterase inhibitor used clinically for thetreatment of Alzheimer's disease (chem. Rec. 2001, 1(1), 63-73). Thecompounds of the invention are thus capable of efficiently counteringscopolamine-induced memory deficiency.

The results of the tests thus show that the compounds of formula (1):

-   -   have high affinity for the human adrenergic receptors of the        alpha-2A subtype;    -   have little or no affinity for the human alpha-2B adrenergic        receptors;    -   generally behave like inverse agonists on the human alpha-2A        adrenergic receptors;    -   are active, in vivo, in an animal model considered as        representative of the memory disorders manifested during        Alzheimer's disease.

As a result, the compounds of the invention and the therapeuticallyacceptable salts thereof are potentially useful as medicinal products,in particular in the treatment of certain progressive neurodegenerativepathologies, for instance Alzheimer's disease.

The administration of the compounds of the invention may be performedvia the oral, nasal, sublingual, rectal or parenteral route. Apreparation of the compounds of the invention is given hereinbelow as anonlimiting formulation example. The ingredients and othertherapeutically acceptable ingredients may be introduced in otherproportions without modifying the scope of, the invention. The term“active ingredient”used in the formulation example hereinbelow refers toa compound of formula (1) or an addition salt or possibly a hydrate ofan addition salt of the compound of formula (1) with a pharmaceuticallyacceptable mineral acid or organic acid.

Example of a Pharmaceutical Composition

Preparation formulation for 1000 tablets each containing 10 mg of theactive ingredient: Active ingredient  10 g Lactose 100 g Wheat starch 10 g Magnesium stearate  3 g Talc  3 g

1. A compound of general formula (1):

in which: (a) R1 represents a hydrogen atom, a fluorine atom or a methoxyl (OCH₃) group and the substituent R1 on the aromatic carbocycle may be in position 2, 3, 4 or 5; (b) R2 represents a hydrogen atom or a methyl group; (c) R3 represents a hydrogen atom, a methyl group, a hydroxyl group (OH) or a methoxyl group (OCH₃); (d) R4 is a hydrogen atom; or (e) R3 and R4 together represent a carbonyl group (C═O); or a salt or hydrate of said salt with a pharmaceutically acceptable mineral acid or organic acid, or the tautomeric or isomeric forms thereof.
 2. The compound of claim 1, selected from the group consisting of: 2-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(1-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(2-fluoro-1-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(3-fluoro-1-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(4-fluoro-1-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(5-fluoro-1-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(6-methyl-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 6a-(4,5-dihydro-1H-imidazol-2-yl)-1a,6a-dihydro-1H-cyclopropa[a]inden-6-one; 6a-(4,5-dihydro-1H-imidazol-2-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]inden-6-ol; 2-(6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(2,6-dimethoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(2-fluoro-6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(3-fluoro-6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; 2-(4-fluoro-6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; and 2-(5-fluoro-6-methoxy-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-4,5-dihydro-1H-imidazole; or a salt or hydrate of said salt with a pharmaceutically acceptable mineral acid or organic acid, or the tautomeric and isomeric forms of each said compound.
 3. A process for preparing a compound according to claim 1 comprising reacting a compound of formula (VII):

in which R1 and R2 have the same meaning as in formula (1), with: (a) methyltriphenylphosphonium bromide in the presence of a base, and the compound formed is reduced with diimide and the reduced compound formed is treated with ethylenediamine to form the compound of formula (X),

which R1 has the same meaning as in formula (1) and R2 is a hydrogen atom or a methyl group; or (b) a reducing agent, and the compound formed is treated with ethylenediamine to form the compound of formula (XII),

in which R1 and R2 have the same meaning as in formula (1); and, optionally, further oxidizing the compound of formula (XII) to form the compound of formula (XIII),

in which R1 and R2 have the same meaning as in formula (1); or (c) a reducing agent, and the compound formed is methylated in the presence of methyl iodide and a silver salt, and the product formed is then treated with ethylenediamine to form the compound of formula (XV),

in which R1 and R2 have the same meaning as in formula (1); or (d) a reducing agent in strong acid medium, and the compound formed is treated with ethylenediamine to form the compound of formula (XVII),

in which R1 and R2 have the same meaning as in formula (1).
 4. A compound of general formula (VII):

in which R1 and R2 have the same meaning as in formula (1).
 5. A process for preparing a compound of formula (VII),

comprising intramolecular cyclization reaction of a compound of formula (VI)

in which R1 represents a hydrogen atom, a fluorine atom or a methoxyl (OCH₃) group and the substituent R1 on the aromatic carbocycle may be in position 2, 3, 4 or 5; and R2 represents a hydrogen atom or a methyl group.
 6. The compound of claim 1, wherein the substituents R2 and 4,5-dihydro-1H-imidazole are in syn-periplanar positions relative to the plane defined by the cyclopropane ring, R1, R3 and R4 have the same meaning as in formula (1) and R2 is a methyl group (CH₃).
 7. The compound of claim 1, wherein R3 and 4,5-dihydro-1H-imidazole are in anti-periplanar positions relative to the plane defined by the indane ring, R1 and R2 have the same meaning as in formula (1), R3 represents a methyl group, a hydroxyl group (OH) or a methoxyl group (OCH₃) and R4 is a hydrogen atom.
 8. The compound of claim 1 in which said compound is in levorotatory or dextrorotatory enantiomeric form.
 9. A medicament comprising a compound as claimed in claim
 1. 10. A pharmaceutical composition, comprising as active ingredient, a compound as claimed in claim 1 and an inert or pharmaceutically acceptable carrier and optionally comprising at least one additional active medicament.
 11. (canceled)
 12. (canceled)
 13. A method of treating Alzheimer's disease, or the evolution of Alzheimer's disease, said treatment comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim
 1. 14. A method of treating Parkinson's disease or Creutzfeld-Jacob disease or strokes, or the evolution of Parkinson's disease or Creutzfeld-Jacob disease or strokes, said treatment comprising administering to a patient in need of such treatment a pharmaceutical composition comprising therapeutically effective amount of a compound of claim
 1. 15. Tautomeric and isomeric forms of a compound of claim
 1. 16. A compound of claim 15 wherein said isomeric forms include enantiomers, mixtures of enantiomers, stereoisomers, racemates and mixtures thereof. 